Enteric coated formulation for bisphosphonic acids and salts thereof

ABSTRACT

Pharmaceutical compositions and methods of using the composition are provided. The pharmaceutical composition comprises an inert core surrounded by an active coating containing one or more bisphosphonic acids or salts thereof, a seal coating surrounding the active coating and an enteric coating surrounding the seal coating. Alendronic acid and alendronate sodium trihydrate are the preferred active ingredients. The composition may be provided in the form of pellets in a capsule or Peltabs. The invention further provides methods for the treatment of disorders caused by the abnormal dissolution or deposition of calcium salts using the inventive compositions.

[0001] This application is a continuation of U.S. application Ser. No.09/669,635, filed Sep. 26, 2000, which claims priority to IndianApplication Nos. 710/BOM/99 and 23/BOM-WTO/99 (709/BOM/99), both ofwhich were filed on Oct. 10, 1999, each of which is incorporated hereinby reference in its entirety.

BACKGROUND OF THE INVENTION

[0002]1. l Field of the Invention

[0003] The present invention relates to a pharmaceutical composition, aprocess of preparing the pharmaceutical composition and a method ofusing the pharmaceutical composition. Specifically, the inventionprovides a pharmaceutical composition containing bisphosphonic acids orsalts thereof for use in the treatment of osteoporosis and otherdisorders caused by the abnormal dissolution or deposition of calciumsalts.

[0004] 2. Background of the Invention

[0005] Methods of preparing bisphosphonic acids are set forth in U.S.Pat. Nos. 3,962,432; 4,054,598; 4,267,108; 4,327,039; 4,407,761;4,621,077; 4,624,947; 4,746,654; 4,922,007; and EPO Patent Pub. No.0,252,504. In particular, methods for the preparation of4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salttrihydrate may be found in U.S. Pat. Nos. 4,407,761 and 4,922,007,respectively.

[0006] The pharmaceutical compositions containing the bisphosphonicacids and salts set forth in the patents listed above have thedisadvantage that the active ingredients are released from themedications almost instantaneously in the upper gastrointestinal tractcausing esophageal discomfort and ulceritis. Thus, the medications haveto be taken on arising for the day and at least 30 minutes before thefirst food, beverage or medication with a full glass (200 ml) of plainwater only. The patients are advised to sit upright for about 30 minutesafter ingestion of the medication and until their first food of the day.Patients are instructed not to take medication at bedtime or beforearising for the day. See Physician's Desk Reference (U.S.) ProductInformation, 1999, p. 1798.

[0007] Several problems have been noted in the preparation of tabletformulations comprising bisphosphonic acid active ingredients, and inparticular with enteric coated forms of these active ingredients. Forexample, U.S. Pat. No. 5,431,920 points out that “standard methods fortablet formulation of bisphosphonic acids suffer from seriousdifficulties.” Thus, particular dry mix formulations are required whenformulating tablets from these active ingredients. In addition, thissame patent points out that “[e]nteric coated dosage forms can sufferfrom stability problems as a result of interactions between the activedrug and the acidic enteric coatings.”

[0008] The present invention solves these problems by providing dosageforms of bisphosphonic acids that do not require formulation intotablets. The dosage forms of the present invention also have improvedstability as compared to prior art formulations.

SUMMARY OF THE INVENTION

[0009] In summary, the invention is related to pharmaceuticalcompositions comprising bisphosphonic acids and salts thereof, theirpreparation and method of use. More specifically, the invention isrelated to pharmaceutical compositions comprising alendronic acid andrelated compounds or salts thereof surrounding an inert core, which iscovered with a seal coating which is further covered with an entericcoating.

[0010] The invention provides pharmaceutical compositions for thetreatment of disorders caused by the abnormal dissolution or depositionof calcium salts. The pharmaceutical compositions of the inventioncomprise an inert core, an active coating containing at least onebisphosphonic acid or salt thereof surrounding the inert core, a sealcoating surrounding the active coating, and an enteric coating aroundthe seal coating. Preferred bisphosphonic acids are selected from thegroup consisting of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid,N-methyl-4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid,4-(N,N-dimethylamino)-1-hydroxybutyl-idene-1,1-bisphosphonic acid,3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid,3-(N,N-dimethylamino)-1-hydroxy-propylidene-1,1-bisphosphonic acid,1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid,and 4-(hydroxymethylene-1,1-bisphosphonic acid)-piperidine. Alendronicacid is a particularly preferred acid and alendronate sodium trihydrateis a particularly preferred salt. Other preferred salts includeetidronate, clodronate, pamidronate, and ibandronate. The compositionspreferably comprise from about 4% to about 40% by weight of at least onebisphosphonic acid or salt.

[0011] Typical enteric coatings for use in the invention include one ormore of hydroxypropyl methylcellulose phthalate, hydroxypropyl celluloseacetyl succinate, cellulose acetate phthalate, polyvinyl acetatephthalate, and methacrylic acid-methyl methacrylate copolymers.

[0012] The active ingredient is coated onto an inert core, such asnonpareils in the form of sugar beads or sugar/starch beads, to form theactive core. The composition may further contain pharmaceuticallyacceptable excipients, diluents, binders, solubilizers, lubricants,disintegrants, etc. In particular, the active core is formed by applyingan active coating to the inert core. The active coating comprises theactive ingredient and may further comprise a polymer. Preferred polymersinclude hydroxypropyl methicellulose, hydroxypropyl cellulose andpolyvinyl pyrrolidone Compositions according to the invention may be inthe form of enteric coated beads in gelatin capsules or Peltabs, and theinvention further provides a process for preparing the claimedcompositions in these forms. The gelatin capsules or Peltabs maythemselves be coated with an enteric coating. The inventive compositionsare preferentially released in the lower gastrointestinal tract uponingestion and thus avoid the disadvantages described above for the priorart.

[0013] The invention also provides methods for the treatment ofdisorders caused by the abnormal dissolution or deposition of calciumsalts by treating a patient in need of such treatment with atherapeutically effective amount of the inventive compositions.Disorders caused by the abnormal dissolution or deposition of calciumsalts that may be treated by the compositions of the invention includeosteoporosis, osteodystrophy, Paget's disease, myositis ossificans,Bechterew's disease, cholelithiasis, nephrolithiasis, urinary calculus,arteriosclerosis, arthritis, bursitis, neuritis and tetany. Thecompositions are particularly useful for the treatment of osteoporosis.

[0014] The above objectives and advantages of the invention areillustrative, and not exhaustive, of those which can be achieved by theinvention. The examples presented herein are non-limiting. Thus, theseand other objectives and advantages of the invention will be apparentfrom the description herein, both as embodied herein and as modified inview of any variations which will be apparent to those skilled in theart.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention provides a pharmaceutical compositioncomprising from about 4% to about 40% by weight of at least one1,1-bisphosphonic acid or salt thereof as an active ingredient. The1,1-bisphosphonic acid is preferably selected from the group consistingof:

[0016] 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

[0017] N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

[0018] 4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;

[0019] 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;

[0020] 3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonicacid;

[0021] 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonicacid; and

[0022] 4-(hydroxymethylene-1,1-bisphosphonic acid)-piperidine.

[0023] In the present invention, the preferred active ingredient is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, i.e. alendronicacid, and, more preferably, its monosodium salt trihydrate, alendronatesodium trihydrate. Other bisphosphonic acids or salts thereof may beused as well, including, for example, etidronate, clodronate,pamidronate or ibandronate. Suitable salts for use in the presentinvention may be formed with, for example, alkali metals, amines andalkanol amines. Salts may be formed by reacting the acid with an alkalimetal hydroxide (e.g. LiOH, NaOH), alkali metal carbonates (e.g.Na₂CO₃), lower alkylamines (e.g. methylamine), lower alkanolamines (e.g.ethanolamine, diethanolamine, triethanolamine) or quaternary ammoniumsalts (e.g. tetramethylammonium hydroxide).

[0024] The invention provides pharmaceutical compositions for oraladministration substantially comprising an inert core, an active coatinghaving at least one bisphosphonic acid or salt thereof surrounding theinert core, a seal coating surrounding the active coating and an acidresistant coating (the “enteric coating”) surrounding the seal coating.The present invention thus is able to resist the acidic environment ofthe stomach and avoid the release of the medication in the uppergastrointestinal tract where it may cause esophageal or stomachdiscomfort or ulceritis. Accordingly, the disadvantages described abovefor the prior art compositions are overcome by the present invention.

[0025] The active core may be achieved by any process known in the artof making pellets, for example, extrusion spheronization, centrifugalcoating, wurster coating, and others. According to the invention, anactive core may be formed on an inert core, such as non-pareils, byapplying an active coating comprising at least one bisphosphonic acid orsalt. The bisphosphonic acids or salts may be mixed withpharmaceutically acceptable components, such as binding agents,solubilizers, lubricants, diluents, disintegrants, etc., prior toforming the active coating on the inert core. In addition, thebisphosphonic acid or salt thereof may be applied with a polymer to forma polymer film. Preferred polymers are hydroxypropyl methylcellulose,hydroxypropyl cellulose and polyvinyl pyrrolidone.

[0026] The active core containing the bisphosphonic acid or salt may becoated with a hydrophilic polymer known in the art, i.e. a seal coating.A suitable seal coating may comprise, for example, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), shellac, cellulose gums and xanthan gums. The sealcoated active core is then further coated with an enteric coating.

[0027] A wide variety of conventional enteric coatings may be employedin the present invention, including, for example: cellulose acetatephthalate; hydroxypropyl methylcellulose phthalate (HPMCP);hydroxypropyl cellulose acetyl succinate; polyvinyl acetate phthalate;copolymerized methacrylic acid/methacrylic acid methyl esters, such asEudragit L 12.5, Eudragit L 100 55, and Eudragit S 100; and mixturesthereof. The enteric coating may further contain conventionalplasticizers, pigments and/or dispersants, including, for example,polyethylene glycols, triacetin, triethyl citrate, Citroflex and dibutylsebacate.

[0028] The enteric coating may be applied in any suitable manner knownin the art, such as, for example, by using a Wurster coater. Whenapplied, the enteric coating may be in the form of an aqueous dispersionin water or other dispersing medium, or in the form of a solution. Ifthe enteric coating is applied in the form of a dispersion or solution,it is preferred that the dispersion or solution be treated with analkali prior to applying the enteric coating to the active core in orderto neutralize at least part of any free acid content. The alkali may be,for example, a carbonate or a hydroxide of sodium, potassium, magnesiumor calcium.

[0029] Bisphosphonic acids and salts thereof that may be incorporatedinto the formulations according to the present invention have been foundto be useful in treating a variety of disorders in mammals. Thesedisorders generally relate to abnormalities of calcium or phosphatemetabolic pathways and particularly to the abnormal dissolution ordeposition of calcium salts. Disorders that have been found to betreatable using bisphosphonic acids and salts include osteoporosis,osteodystrophy, Paget's disease, myositis ossificans, Bechterew'sdisease, cholelithiasis, nephrolithiasis, urinary calculus,arteriosclerosis, arthritis, bursitis, neuritis and tetany. Thepharmaceutical compositions prepared according to the invention areparticularly useful for the treatment of osteoporosis.

[0030] The dosages of the compounds may be variable and depend on theparticular condition to be treated and other factors including theseverity of the illness, duration of treatment and the identity of theparticular compounds being used. Effective dosages preferably range fromabout 0.05 to about 500 mg/kg body weight/day and more preferably fromabout 1 to about 50 mg/kg/day. The dosage is typically administered in 4individual doses. After initial treatment with a relatively high dose,it may be necessary to continue treatment at a lower dose to maintainthe beneficial effects of the compounds.

[0031] Pharmaceutical compositions according to the present inventionmay further comprise one or more additives. Examples of particularlyuseful additives include diluents to aid dissolution of thepharmaceutically active ingredient and lubricants to aid flow of theactive ingredient during manufacture. The diluent may be, for example,lactose. The lubricant may be, for example, magnesium stearate and/ortalcum. It will be appreciated that the pharmaceutical compositions ofthe invention may also contain any one or more other additivesconventionally used in the formulation of pharmaceutical compositions.Additives may include excipients known in the art of manufacturingcapsules and Peltabs, such as lactose, microcrystalline cellulose,dicalcium phosphate, starch, sugar, and disintegrants (e.g., starch andderivatives of starch, sodium carboxy methyl cellulose and itsderivatives, and crospovidone).

[0032] The pharmaceutical composition of the present invention may takethe form of Peltabs or pellets in a capsule. The disadvantages offorming tablets containing bisphosphonic acids described in the priorart are thus avoided. A further advantage of the invention is that thecapsule or Peltab can break down in the stomach releasing the entericcoated beads which can then move freely into the lower gastrointestinaltract. This avoids problems associated with a tablet sitting in thestomach until the digestion of food opens the pyloric sphincter and thetablet passes into the duodenum. In addition, the use of small beadsdecreases the risk of large local concentrations of the activeingredients coming into contact with mucosal or epithelial tissue.

[0033] The relative release rate of the active ingredient from theenteric coated beads may be varied by changing one or more of (a) theactive ingredient, (b) the composition and thickness of the entericcoating; (c) the composition and thickness of the seal coating; (d) theamount of active ingredient in individual beads; and (e) the size of thebeads. Thus, the composition may be adjusted to allow release in thesmall intestine, the large intestine or throughout the intestinal tract.In addition, release rates can be controlled by applying an additionalenteric coating over the gelatin capsule or over the Peltab after itsformulation.

[0034] According to one embodiment of the present invention, the activecore comprises an inert core, such as nonpareils provided in the form ofsugar beads or sugar/starch beads, as well as the bisphosphonic acid orsalt. Inert cores may be approximately 0.6 mm in diameter and arepreferably from about 0.2 mm to about 1.0 mm in diameter. Thebisphosphonic acid or salt thereof is loaded onto each of a plurality ofthe inert cores as an active coating. The bisphosphonic acid or salt mayalso be mixed with one or more additives before being loaded onto theinert cores. The additives may include, for example, a solubilizerand/or a lubricant. The bisphosphonic acid or salt (together with anyadditives) can be sprayed onto the inert core with a binder in acentrifugal coating apparatus. A polymer, such as HPMC, HPC or PVP maybe applied in conjunction with the application of the active ingredientto form the active coating as a polymer film. A seal coating is appliedaround the active core, and the enteric coating is then provided aroundthe seal coating on each of the active cores. This embodiment of theinvention is particularly useful when the capsule form of thepharmaceutical composition is desired. A plurality of pellets containingthe bisphosphonic acid or salt loaded on inert cores and coated withseal coatings and enteric coatings may be included in a capsule shell.

[0035] Another embodiment of the present invention is particularlyuseful if the Peltab form of the pharmaceutical composition is desired.In this embodiment, the active cores of the pellets comprise nonpareilsprovided in the form of sugar beads or sugar/starch beads onto which thebisphosphonic acid or salt has been loaded as described above. A sealcoating is applied around the active core of each of the pellets, andthe enteric coating provided around the seal coating on each of theactive cores. A plurality of these pellets, which may be combined withone or more conventional additives, such as disintegrants and binders,may then be compressed into tablets generally known as Peltabs.

[0036] The following examples illustrate the invention. In each case,the active drug is a bisphosphonic acid or salt thereof, unlessindicated otherwise. While sucrose (sugar) is the illustrated bindingagent, other binding agents, such as polyvinylpyrrolidone, shellac orxanthan gum, may be used instead. Examples 1 through 3 present generalexamples of the preparation of pharmaceutical compositions containingbisphosphonic acids or salts thereof. Although, in principal, anybisphosphonic acid or salt may be used in the formulations, theformulations are particularly useful for preparing pharmaceuticalcompositions comprising alendronate sodium trihydrate.

EXAMPLE 1

[0037] Capsules:

[0038] A plurality of pellets containing the active drug are preparedfrom the following materials: Core: Nonpareil seeds 95 mg Active drug13.03 mg Sucrose 31.97 mg Corn starch 32 mg Talcum 10 mg HPMC 1 mg 183mg Water: as required Seal coating: HPMC 7.2 mg Talc 1.4 mg Propyleneglycol 1.4 mg 10 mg Water: as required Isopropyl alcohol: as requiredEnteric coating: Eudragit L 100-55 22.50 mg Sodium hydroxide 0.320 mgTriethyl citrate 2.270 mg Talc 22.50 mg Titanium dioxide 2.18 mg Aerosil0.23 mg 50.00 mg Water: as required

[0039] The active drug, the sucrose, the corn starch and the talcum areblended thoroughly to yield a dusting powder. The nonpareil seeds areloaded into a centrifugal coater and then coated with the dusting powderwhile spraying the HPMC (hydroxypropyl methyl cellulose) solution. Thisprocedure results in the production of a plurality of discrete pelletscontaining the active ingredient. The pellets so obtained are driedusing conventional tray dryers or fluid bed dryers up to an outlettemperature of 45° C. These pellets are then seal coated using HPMCsolution and further enteric coated in a suitable Wurster coater. Thepellets are then included in a capsule shell.

EXAMPLE 2

[0040] Capsules:

[0041] A plurality of pellets containing the active drug are preparedfrom the following materials: Core: Nonpareil seeds 95 mg Active drug13.03 mg Sucrose 31.97 mg Corn starch 32 mg Talcum 10 mg HPMC 1 mg 183mg Water: as required Seal coating: HPMC 7.2 mg Talc 1.4 mg Propyleneglycol 1.4 mg 10 mg Water: as required Isopropyl alcohol: as requiredEnteric coating: Eudragit L 100-55 18.00 mg Sodium hydroxide 0.25 mgTriethyl citrate 1.81 mg Talc 18.00 mg Titanium dioxide 1.75 mg Aerosil0.19 mg 40.00 mg Water: as required.

[0042] The active drug, the sucrose, the corn starch and the talcum areblended thoroughly to yield a dusting powder. The nonpareil seeds areloaded into the centrifugal coater and then coated with the dustingpowder while spraying the HPMC solution. This procedure results in theproduction of a plurality of discrete pellets containing the activeingredient. The pellets so obtained are dried using conventional traydryers or fluid bed dryers up to an outlet temperature of 45° C. Thesepellets are then seal coated using HPMC solution and further entericcoated in a suitable Wurster coater. The pellets are then included in acapsule shell.

EXAMPLE 3

[0043] Peltabs:

[0044] A plurality of particles containing the active drug are preparedfrom the following materials: Core: Nonpareil seeds 110.07 mg Activedrug 13.03 mg Sucrose 35.90 mg Corn starch 21.00 mg Talcum 2 mg HPC-LKlucel 1 mg 183 mg Water: as required Seal coating: HPMC 7.2 mg Talc 1.4mg Propylene glycol 1.4 mg 10 mg Water: as required Isopropyl alcohol:as required Enteric coating: Eudragit L 100-55 22.50 mg Sodium hydroxide0.320 mg Triethyl citrate 2.270 mg Talc 22.50 mg Titanium dioxide 2.18mg Aerosil 0.23 mg 50.00 mg Water: as required Microcrystallinecellulose 50 mg Croscarmellose sodium 7 mg 57.00 mg

[0045] The active drug, the sucrose, the corn starch and the talcum areblended thoroughly to yield a dusting powder. The nonpareil seeds areloaded into the centrifugal coater and then coated with the dustingpowder while spraying the HPC-L Klucel (hydroxypropyl cellulose)solution. This procedure results in the production of a plurality ofdiscrete pellets containing the active ingredient. The pellets soobtained are dried using conventional tray dryers or fluid bed dryers upto an outlet temperature of 45° C. The pellets are then seal coatedusing the HPMC solution and further enteric coated in a suitable Wurstercoater. The pellets are then suitably diluted with binders anddisintegrants and compressed by conventional means to form tablets.

[0046] The embodiments and non-limiting examples illustrated anddiscussed in this specification are intended only to teach those skilledin the art the best way known to the inventors to make and use theinvention. Nothing in this specification should be considered aslimiting the scope of the present invention.

What is claimed is:
 1. A pharmaceutical composition for the treatment ofa disorder caused by the abnormal dissolution or deposition of calciumsalts comprising: an inert core, an active coating surrounding the inertcore, a seal coating surrounding the active coating, and an entericcoating around said seal coating; wherein the active coating comprisesat least one bisphosphonic acid or salt thereof.
 2. The compositionaccording to claim 1, wherein the at least one bisphosphonic acid isselected from the group consisting of:4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid;N-Methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;4-(N,N-Dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;3-Amino-1-hydroxypropylidene-1,1-bisphosphonic acid;3-(N,N-Dimethylamino)-1-hydroxypropylidene-1,1 -bisphosphonic acid;1-Hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid;4-(Hydroxymethylene-1,1-bisphosphonic acid)-piperidine; and saltsthereof.
 3. The composition according to claim 1, wherein the at leastone bisphosphonic acid is alendronic acid.
 4. The composition accordingto claim 1, wherein the at least one bisphosphonic acid or salt thereofis selected from the group consisting of alendronate sodium trihydrate,etidronate, clodronate, pamidronate, and ibandronate.
 5. The compositionaccording to claim 1, wherein the composition comprises from about 4% toabout 40% by weight of the at least one bisphosphonic acid or saltthereof.
 6. The composition according to claim 1, wherein the sealcoating comprises one or more hydrophilic polymers selected from thegroup consisting of hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinyl pyroolidone, shellac, cellulose gum and xanthangum.
 7. The composition according to claim 1, wherein the entericcoating is selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropyl cellulose acetyl succinate,cellulose acetate phthalate, polyvinyl acetate phthalate, methacrylicacid-methyl methacrylate copolymers, and mixtures thereof.
 8. Thecomposition according to claim 7, wherein the methacrylic acid-methylmethacrylate copolymer is selected from the group consisting of EudragitL 12.5, Eudragit L 100 55, Eudagrit S 100 and mixtures thereof.
 9. Thecomposition according to claim 1, wherein the inert core comprises sugarbeads or sugar/starch beads.
 10. The composition according to claim 1,wherein the active coating further comprises at least one of asolubilizer and a lubricant.
 11. The composition according to claim 1,wherein the active coating comprises a polymer film comprising a mixtureof at least one bisphosphonic acid or salt thereof and a polymer. 12.The composition according to claim 11, wherein the polymer is selectedfrom the group consisting of hydroxypropyl methylcellulose,hydroxypropyl cellulose and polyvinyl pyrrolidone.
 13. The compositionaccording to claim 1, further comprising a binder.
 14. A capsule orPeltab comprising a plurality of pellets each of which comprises acomposition according to claim
 1. 15. The composition according to claim1, wherein the composition releases the at least one bisphosphonic acidor salt thereof only in the lower gastrointestinal tract of a human oranimal upon ingestion.
 16. The composition according to claim 1, whereinthe disorder caused by the abnormal dissolution or deposition of calciumsalts is selected from the group consisting of osteoporosis,osteodystrophy, Paget's disease, myositis ossificans, Bechterew'sdisease, cholelithiasis, nephrolithiasis, urinary calculus,arteriosclerosis, arthritis, bursitis, neuritis and tetany.
 17. Thecapsule or Peltab of claim 14, further comprising an enteric coatingover said capsule or Peltab.
 18. A method for treating a disorder causedby the abnormal dissolution or deposition of calcium salts comprising:providing a pharmaceutical composition; and administering an effectivedose of the pharmaceutical composition to a person in need thereof;wherein the pharmaceutical composition comprises an inert core, anactive coating surrounding the inert core, a seal coating surroundingthe active coating, and an enteric coating around said seal coating; andwherein the active coating comprises at least one bisphosphonic acid orsalt thereof.
 19. The method according to claim 18 wherein the at leastone bisphosphonic acid is selected from the group consisting of:4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid;N-Methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;4-(N,N-Dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;3-Amino-1-hydroxypropylidene-1,1-bisphosphonic acid;3-(N,N-Dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;1-Hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid;4-(Hydroxymethylene-1,1-bisphosphonic acid)-piperidine; and saltsthereof.
 20. The method according to claim 18, wherein the at least onebisphosphonic acid is alendronic acid.
 21. The method according to claim18, wherein the at least one bisphosphonic acid salt is selected fromthe group consisting of alendronate sodium trihydrate, etidronate,clodronate, pamidronate, and ibandronate.
 22. The method according toclaim 18, wherein the disorder caused by the rmal dissolution ordeposition of calcium salts is selected from the group consisting ofosteoporosis, osteodystrophy, Paget's disease, myositis ossificans,Bechterew's disease, cholelithiasis, nephrolithiasis, urinary calculus,arteriosclerosis, arthritis, bursitis, neuritis and tetany.